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Infection and Immunity, January 2004, p. 82-88, Vol. 72, No. 1
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.1.82-88.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Tissue Inhibitor of Metalloproteinase 1 Activates Normal Human Granulocytes, Protects Them from Apoptosis, and Blocks Their Transmigration during Inflammation

Milan Chromek,1,2 Kjell Tullus,3,4 Joachim Lundahl,5 and Annelie Brauner1*

Department of Clinical Microbiology,1 Astrid Lindgrens Children's Hospital,3 Department of Immunology and Transfusion Medicine, Karolinska Hospital, Stockholm, Sweden,5 Department of Pediatrics, Comenius University Medical School, Bratislava, Slovakia,2 Great Ormond Street Hospital for Children, London, United Kingdom4

Received 30 May 2003/ Returned for modification 2 September 2003/ Accepted 10 October 2003

Urinary levels of tissue inhibitor of metalloproteinase 1 (TIMP-1) higher than those of matrix metalloproteinase 9 (MMP-9) during acute pyelonephritis have previously been associated with a higher degree of acute inflammation and of postinfective renal scarring. The aim of the present study was to evaluate possible mechanisms by which TIMP-1 could affect the scarring process already during the acute phase of inflammation. The growth of Escherichia coli, bactericidal activity of fresh human blood, and respiratory burst, spontaneous apoptosis, and trans-basement membrane migration of normal human granulocytes were studied in vitro in the presence of different concentrations of recombinant human TIMP-1. To imitate the "normal" environment during inflammation in the kidney, granulocytes were also incubated with a conditioned medium from E. coli-stimulated renal epithelial cells. In order to compare our data with the in vivo situation, blood and urinary leukocyte levels were analyzed for 40 children with acute pyelonephritis, together with urinary MMP-9 and TIMP-1 levels. TIMP-1 at a concentration of 500 ng/ml increased the bactericidal activity of blood, increased the respiratory burst of granulocytes, decreased phosphatidylserine exposure and caspase 3 activity, which are features of spontaneous apoptosis, and inhibited granulocyte transmigration. Moreover, in the patients with pyelonephritis, MMP-9/TIMP-1 ratios in urine correlated with the degree of leukocyte transmigration. Thus, our data suggest that TIMP-1 specifically blocks the transmigration of granulocytes into urine. Entrapped and activated granulocytes, protected from apoptosis, might excessively destroy renal parenchyma and thus contribute to the pathogenesis of renal scarring following acute pyelonephritis.

* Corresponding author. Mailing address: Department of Clinical Microbiology, Microbiology and Tumorbiology Center, Karolinska Hospital, S-171 76 Stockholm, Sweden. Phone: 46 8 5177 0000 or 46 8 5177 3914. Fax: 46 8 308099. E-mail: Annelie.Brauner{at}ks.se.

Editor: F. C. Fang

Infection and Immunity, January 2004, p. 82-88, Vol. 72, No. 1
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.1.82-88.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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